title: The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice.
abstract: Acute kidney injury (AKI) caused by ischemia-reperfusion is a major clinical problem in both native and transplanted kidneys. We had previously shown that deficiency of Nrf2, a potent bZIP transcription factor that binds to the antioxidant response element, enhances susceptibility to experimental ischemic AKI. Here we further explored the role of Nrf2 in AKI by amplifying Nrf2 activation in vivo and in vitro with the synthetic triterpenoid CDDO-imidazolide. Mice treated with CDDO-imidazolide and undergoing experimental bilateral ischemic AKI had improved survival and renal function. Treated mice had improved renal histology with a decrease in tubular injury, as well as a decrease in proinflammatory cytokine and chemokine production compared with vehicle-treated mice. In an exploration of protective mechanisms, we found an upregulation of Nrf2 target antioxidant genes in CDDO-imidazolide-treated mouse kidneys. Furthermore, Nrf2-deficient mice treated with CDDO-imidazolide had no significant improvement in mortality, renal function or histology, proinflammatory cytokine gene expression, and no significant increase in antioxidant gene expression. In vitro studies demonstrated that the renal epithelial cells were likely an important target of CDDO-imidazolide. Thus, activation of Nrf2 signaling with CDDO-imidazolide confers protection from AKI, and presents a new therapeutic opportunity for this common and serious condition.
authors.affiliation: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Manchang
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, College of Medicine, University of Illinois, Chicago, Illinois, USA.
authors.forename: Narsa M
authors.initials: NM
authors.lastname: Reddy
authors.affiliation: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Higbee
authors.affiliation: Department of Pediatrics, College of Medicine, University of Illinois, Chicago, Illinois, USA.
authors.forename: Haranatha R
authors.initials: HR
authors.lastname: Potteti
authors.affiliation: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Noel
authors.affiliation: Departments of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Racusen
authors.affiliation: Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.affiliation: Department of Pediatrics, College of Medicine, University of Illinois, Chicago, Illinois, USA.
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
authors.affiliation: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Rabb
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D000860:Hypoxia / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D016207:Cytokines; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009828:Oleanolic Acid